Fructose-1,6-bisphosphatase (FBPase) is a rate-limiting enzyme of gluconeogenesis that is allosterically regulated by AMP and responsible for the hydrolysis of Fructose-1,6-bisphosphate to Fructose-6-phosphate. FBPase AMP site inhibitors have valuable pharmacological properties suitable in both human and veterinary medicine.
Inhibitors of FBPase and of the production of Fructose-6-phosphate that is reversibly converted to Glucose-6-phosphate, a metabolite which represents a common precursor for diverse essential metabolic pathways generating glucose, glycogen, ATP, amino acids, nucleotides, NADPH and so forth, have a large variety of indications related to the management of body homeostasis and the prevention of metabolic dysfunctions. For example, inhibitors of FBPase and of gluconeogenesis in the liver, or in other organs capable of producing glucose like kidney or intestine, are hypoglycaemic agents and are indicated for the treatment and/or the prophylaxis of disorders of glucose homeostasis, such as Diabetes Mellitus, in particular Type II and Type I Diabetes Mellitus (NIDDM and IDDM), Impaired Fasting Glucose (IFG), Impaired Glucose Tolerance (IGT), and for the prevention of the progression of disorders of the Metabolic Syndrome (MetS, also described as Syndrome X or Insulin Resistance Syndrome) which most important components are insulin resistance (with or without IGT), obesity, dyslipidemia, hypertension, prothrombic and proinflammatory states. As such, compounds of the present invention are also indicated for the prevention and/or the treatment of diabetic complications or diabetic-associated diseases such as cardiomyopathy, macrovascular atherosclerotic disorders, including coronary, cerebrovascular and peripheral artery diseases, microvascular diseases including retinopathy, cataracts, blindness and nephropathy, neuropathy (peripheral neuropathy and sympathetic nerve disorders), diabetic necrosis, infection or depression, and so forth.
In addition, inhibitors of FBPase that cause the accumulation of Fructose-1,6-bisphosphate capable for increasing the glycolytic production of ATP have cytoprotective effects as anti-ischaemic agents and are useful for preventing ischaemia-induced tissue damage. Therefore, inhibitors of FBPase can be used in a variety of ischaemic and inflammatory conditions where acute management of tissue injury could be beneficial such as surgical trauma, myocardial infarction, congestive heart failure, stroke, sickle cell disease, and so forth, and have further utility in cardioprotection, in improving cardiac function and tolerance to exercise, in improving red-blood cells and pulmonary endothelial functions, in organ preservation in transplants, and so forth. As such, inhibitors of FBPase can also be used to treat asthma attacks, hypertension, atherosclerosis and so forth, and in the management of certain excess glycogen storage diseases such as McArdle disease (GSD-Type V) and others.
Also as inhibitors of FBPase, and thereby of the production from the gluconeogenic pathway of Fructose-6-phosphate and Glucose-6-phosphate that serve as precursors for other pathways of hexose metabolism (e.g. synthesis of amino-sugars/hexosamines that are used for the biosynthesis of glycoproteins, glycosphingolipids or glycosaminoglycans, and uronic acid pathway that leads to glucuronate, a precursor of proteoglycans and conjugated glucuronides, and so forth), or for the pentose phosphate pathway (PPP, also called phosphogluconate pathway) which provides the carbon source for common aromatic biosynthetic pathways (nucleotides and amino-acids synthesis) and generates NADPH for reductive biosyntheses (lipogenesis, steroidogenesis), such inhibitors can have further utility in the prevention and/or the management of a large set of diseases including obesity, atherosclerosis, inflammation, Alzheimer disease, cancer or respiratory disorders such as excess mucus production and allergic asthma, excess surfactant synthesis, cystic fibrosis, and so forth.
A reference which relates to inhibition of fructose 1,6-bisphosphatase and reduction of excessive endogenous glucose production and attenuates hyperglycemia is Zucker diabetic fatty rats. van Poelje, Paul D.; Potter, Scott C;. Chandramouli, Visvanathan C.; Landau, Bernard R.; Dang, Qun; Erion, Mark D. Departments of Biochemistry and Medicinal Chemistry, Metabasis Therapeutics, La Jolla, Calif., USA. Diabetes (2006), 55(6), 1747-1754. Publisher: American Diabetes Association.
A reference which relates to fructose 1,6-bisphosphatase inhibitors as preventives for the onset of diabetes is Yoshida, Taishi; Okuno, Akira. (Sankyo Company, Limited, Japan). PCT Int. Appl. (2004), 50 pp. WO 2004009118 A1 20040129
Another reference relating to bisamidate phosphonate prodrugs of FBPase inhibitors for use as antidiabetics is Jaing, Tao; Kasibhatla, Srinivas Rao; Reddy, Raja K. (Metabasis Therapeutics, Inc., USA). PCT Int. Appl. (2001) WO 2001047935.
There is a need, therefore, for novel FBPase inhibitors for the treatment of diseases and disorders.